Abstract
Adjuvant 5-fluorouracil (5-FU)-based chemotherapy, including FOLFOX (5-FU, leucovorin, and oxaliplatin), is recommended for colorectal cancer. However, intestinal mucositis remains a common adverse effect for which no effective preventive strategies are available. To develop a convenient and novel way to alleviate mucositis, we investigated the effect of Lactobacillus casei variety rhamnosus (Lcr35) on FOLFOX-induced mucosal injury. BALB/c mice subcutaneously injected with syngeneic CT26 colorectal adenocarcinoma cells were orally administered Lcr35 daily before, during, and after 5-day injection of FOLFOX regimen, for 14 days. The following methods were used: diarrhea score for toxicity, ELISA for cytokine production, histopathology for intestinal injury, immunohistochemistry for apoptosis/proliferation and regulatory proteins, RT-PCR for cytokine mRNA expression, and DNA sequencing for fecal gut microbiota. FOLFOX administration to colorectal cancer-bearing mice significantly inhibited tumor growth and the accompanying marked diarrhea and intestinal injury histologically characterized by the shortening of villi and destruction of intestinal crypts. Preventive administration of Lcr35 dose-dependently reduced the severity of diarrhea and intestinal mucositis without affecting the anti-tumor effect of FOLFOX. The numbers of apoptotic, NF-κB-, and BAX-activated cells increased after FOLFOX, and these responses were mitigated by Lcr35. TNF-α and IL-6 upregulation by FOLFOX treatment was attenuated by Lcr35. The fecal gut microbiota composition of Firmicutes and Bacteroidetes disturbed by FOLFOX was significantly reversed by Lcr35 toward a preferential profile. In conclusion, the oral probiotic Lcr35 prevented FOLFOX-induced intestinal mucositis in colorectal cancer-bearing mice. The putative mechanism might involve modulation of gut microbiota and proinflammatory responses with suppression of intrinsic apoptosis in intestinal injury.
Highlights
Gastrointestinal toxicity due to chemotherapeutic drugs is a major cause of morbidity and mortality in cancer patients
We further investigated the protective effect of Lactobacillus casei variety rhamnosus on intestinal mucosal injury induced by 5-FU-based chemotherapy (FOLFOX) in subcutaneously injected colon cancer mice
The pair-reads were merged into amplicon sequences using PEAR (Zhang et al, 2014) and these amplicon sequences were checked for the existence of the primers, duplicates were removed, and short sequences and chimeric reads were filtered out to generate effective reads
Summary
Gastrointestinal toxicity due to chemotherapeutic drugs is a major cause of morbidity and mortality in cancer patients. Lesions associated with mucositis result in pain, decreased quality of life, increased length of hospitalization, higher risk of infection, and modification of anti-neoplastic treatment regimens (Sonis et al, 2004; Sharma et al, 2005; Lee et al, 2014). The pathophysiology of chemotherapy-induced mucositis remains unclear and involves a complex and dynamic array of biological events (Logan et al, 2007; Lee et al, 2014). The pathophysiology might include decreased villi length and disruption of crypt cell homeostasis, and several pathogenic elements are involved, including direct toxicity, a change in the balance of bowel microbial flora, oxidative stress, apoptosis, hypoproliferation, and abnormal inflammation. No well-established or up-to-date therapeutic strategy is available to manage chemotherapy-induced intestinal mucositis (Sharma et al, 2005). The development of an effective intervention against chemotherapy-related mucositis is urgently needed for oncological supportive care
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